Cell stem cellJun 16, 2026

ZNF512B protects genetic control areas to reduce aging-related inflammation

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 18, 2026

Abstract

ZNF512B is identified as a key suppressor of the senescence-associated secretory phenotype (SASP).

Loss of ZNF512B leads to DNA damage and activates inflammatory signaling pathways.
ZNF512B functions by promoting DNA repair specifically at regulatory genomic regions, which limits SASP activation.
In human neuromuscular organoids, a deficiency of ZNF512B results in inflammation and cytokine secretion similar to amyotrophic lateral sclerosis (ALS).
Overexpression of ZNF512B in vivo decreases DNA damage and inflammation after acute liver injury.
These findings suggest that ZNF512B plays a role in maintaining genome integrity and regulating inflammation.

Simplified

Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc-finger protein ZNF512B as a key suppressor of the SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA-damage sites via distinct zinc-finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling amyotrophic lateral sclerosis (ALS)-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity, suppressing SASP and inflammation.